Pomeroy-Black M J, Jortner B S, Ehrich M F
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, 1 Duckpond Drive, Blacksburg, VA 24061, USA.
Neurotox Res. 2007 Feb;11(2):85-91. doi: 10.1007/BF03033387.
Exposure to OP compounds that inhibit neurotoxic esterase (NTE) induces a delayed neuropathy (OPIDN) characterized by Wallerian-like degeneration of long axons in certain animals, including humans. Pope et al. (Toxicol. Lett. 75:111-117, 1995) found that neurite outgrowth occurred following the addition of spinal cord extracts from chickens with active OPIDN to neuroblastoma cells, suggesting growth factor expression during the neuropathy. We hypothesized that, shortly after exposure to a neuropathic OP compound, the central nervous system (CNS) attempts to recover from the toxic insult through upregulation of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in susceptible regions of the nervous system. We hypothesized that such upregulation is transient and cannot be sustained. To test this hypothesis, we exposed 10-week-old chickens to a neuropathic OP compound (PSP, 2.5 mg/kg), a non-neuropathic OP compound (paraoxon, 0.10 mg/kg), and vehicle (DMSO, 0.5 ml/kg) intramuscularly. By day 8, all PSP-treated birds demonstrated clinical signs of OPIDN. We sacrificed chickens by pentobarbital overdose at 4, 8, 24, and 48 hours, and 5 and 10 days post-exposure and confirmed NTE inhibition in birds treated with PSP 4 and 24 hours earlier. Enzyme-linked immunosorbant assays indicated that NGF, BDNF, and NT-3 are found in chicken lumbar spinal cord after exposure to a neuropathic OP compound. However, exposure to the neuropathic OP compound, PSP, did not preferentially elevate levels of NGF, BDNF, and NTE compared to the non-neuropathic OP compound, paraoxon. This suggests that these neurotrophins alone do not contribute to a sustained regenerative effort in the CNS.
接触抑制神经毒性酯酶（NTE）的有机磷化合物会诱发迟发性神经病（OPIDN），其特征是在包括人类在内的某些动物中，长轴突出现类华勒氏变性。波普等人（《毒理学快报》75:111 - 117，1995年）发现，将患有活动性OPIDN的鸡的脊髓提取物添加到神经母细胞瘤细胞后，出现了神经突生长，这表明在神经病过程中存在生长因子表达。我们推测，在接触神经性有机磷化合物后不久，中枢神经系统（CNS）会试图通过上调神经系统易感区域的神经营养因子神经生长因子（NGF）、脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）来从毒性损伤中恢复。我们推测这种上调是短暂的，无法持续。为了验证这一假设，我们给10周龄的鸡肌肉注射神经性有机磷化合物（PSP，2.5毫克/千克）非神经性有机磷化合物（对氧磷，0.10毫克/千克）和赋形剂（二甲基亚砜，0.5毫升/千克）。到第8天，所有接受PSP处理的鸡都表现出OPIDN的临床症状。我们在接触后4、8、24和48小时以及5天和10天，通过戊巴比妥过量处死鸡，并确认在4小时和24小时前用PSP处理的鸡中NTE受到抑制。酶联免疫吸附测定表明，接触神经性有机磷化合物后，鸡的腰脊髓中可检测到NGF、BDNF和NT-3。然而，与非神经性有机磷化合物对氧磷相比，接触神经性有机磷化合物PSP并没有优先提高NGF、BDNF和NTE的水平。这表明仅这些神经营养因子并不能促进中枢神经系统持续的再生努力。
